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How does a T cell know that a pathogen is inside a cell?
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Receptors and ligands
The receptor is the T cell receptor
The ligandis a molecular complexthat the infected cell puts on itscell surface -A complex of a MHC molecule anda peptide from the pathogen.
Engagement of the TCR by MHCand peptide results in stimulationof the T cell, cytokine productionand stimulation of the macrophageto become more cytotoxic.
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( )Major Histocompatibility Complex MHCMolecules
( )Human MHC HLA Human Leukocyte Antigens
Stimulation of immune system- Transplanted tissue or against host ( )GVH
- Autoimmunity- Against pathogens
Steer the immune system to most effective response- Humoral extracellular microorganisms- Cellular intracellular microorganisms Education of T cells in thymus
- -Self from non self- -Elimination of self reactive T cells
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Ig vs. TCR
Similarities
Constant region
Variable region
Part of the same multigenefamily
Differences
Abs can be solubleTCR Cell-associated
Ligands recognized
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i sc on ti nu ou s o r o nf or ma ti on al e pi to pe s
holevirus
inearepi topes
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InER
InER
InER
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MHC class I expression
is induced by type Iinterferons
Plasmodium
MHC CLASS IITRANSACTIVATOR
BARELYMPHOCYTESYNDROME
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JUST REMEMBER THE NUMBER 8
MHC I x CD8 = 8
MHC II x CD4 = 8
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TAP
I
I
I
I
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MHC and Transplantation
The immune system (T cells) responds to non-self MHC on transplanted donor cells the same way that it responds to self-MHC with foreign peptide.
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olymorphism inMHC
120
250
70
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- MHC alleles differ from each other by 1 50 amino acids mostly in antigen binding cleft
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Allergy/Type I
Hypersensitivity
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Hypersensitivity Defined by two immunologists called
Coombs and Gell They originally classified
hypersensitivity into Types I-IV These can occur in isolation but
diseases may present with amixture of hypersensitivityresponses
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Hypersensitivity
Type I Hypersensitivity: IgE mediatedactivation of mast cells
Type II Hypersensitivity: antibodymediated binding of cell or tissuebound antigens
Type III Hypersensitivity: antibodymediated immune complexes
Type IV Hypersensitivity: T cellmediated DTH
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TYPES OF HYPERSENSITIVITYGells and Coombs classification
Type 1 - Immediate reaction - Ig Eantibodies
Type 2 - Cytotoxicreaction - IgG &IgM Type 3 Immune complexes IgG &
IgM Type 4 Delayed reaction 48 hrs T-
cell mediated
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Type I HypersensitivityReactions
This is the immunological processwhich brings about Anaphylaxis
Allergies The most common disorder of
immunity About 20% of individuals in the US
have some type of allergy
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Hypersensitivity
It is the typical response that occurs in
Hay fever (allergic rhinitis) : Edema,irritation, mucus in nasalmucosa
Asthma: bronchial constriction ,edema,
mucus prod. Atopic dermatitis (eczema) Hives (urticaria) is usually associated with
Type I Hypersensitivity Can be caused by other mechanisms
An individual who has an allergy is atopic(out of place)
Systemic anaphylaxis: bronchialconstriction, vasodilation
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Eczema
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Type I HypersensitivityMechanism
Production of IgE by B cells Under Th2 control
IgE binds to Fc RI on mast cells andbasophils
Re-introduced antigen binds (cross-links) to IgE
Mast cell/basophil degranulationoccurs
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Type I Hypersensitivity If the above reaction takes place in the
skin the response is a wheal and flarereaction
This is seen in urticaria (hives) The reaction is called immediate It takes about 5' to occur and
subsides within an hour
Sometimes there is a further late phasereaction that o ccurs about 2 hours laterand peaks at about 24 hours
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Wheal and Flare
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Urticaria A vascular
reaction of theskincharacterizedby erythema(flare) and
wheal formationdue to localizedincrease of vascular
permeability
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Urticaria
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IgE Some diseases are characterized by very
high IgE levels Atopic eczema
Levels up to 30,000 IU In many cases it is IgE specificity which is
important i.e., what is the allergen
Measure by a skin prick test Measure by a RAST
(radioallergosorbent test)
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Skin prick test
This involves placing a small drop of a solution of the allergen to betested onto the patients skin
Usually the back or arms Then inserting this into the intra-
epidermis Using a hypodermic needle
A wheal and flare response would bea positive result
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Skin prick test
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Regulation of IgE Synthesis
This is induced by cytokines actingupon B cells to induce antibodyclass switching Secondary immune response
IL-4 and IL-13 appear to induce theproduction of IgE
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Common Allergens
Airborne Grass Pollen Tree Pollen
Mold Spores Animal Dander House Dust
Mite
Foods Fish/shellfish Eggs
Peanuts Milk Gluten
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A patient is stung by a bee for the first time andpresents with a wheal and flare response. What will
your course of action be?
A.Give immediateepinephrine to preventanaphylactic shock
B.Give the patient aprescription forepinephrine in casethey are stung again
C.Give the patient a
prescription for anti-histaminesD.Admit the patient to ER
and monitor thepatients vital signs
E. Prescribe a to ical
00
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Mast Cells and Basophils
Mast cells are tissue bound cells thatare found throughout the body
There are differing types of mastcells in humans They vary morphologically,
biochemically, and in their tissue
distribution
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Mast Cell
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Eosinophil
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Eosinophils
Regulation of eosinophils appears tobe partially controlled by IL-5
Evidence suggests a major role foreotaxin A chemokine
During an acute helminth infection Numbers of circulating and local
eosinophils increase
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Mast Cell Activation Activation of mast cells and basophils
results in Exocytosis of granules containing pre-
formed mediators Synthesis of new mediators Secretion of cytokines, such as:
IL-4 IL-5 IL-13
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Mast Cell Activation
Preformed mediators includebiogenic amines
Histamine
Heparin Chemotactic factors, serotonin Tryptase and chymase
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Histamine Binds to target cell receptors called H 1 - H 4
and causes a number of effects such as Smooth muscle contraction resulting in, forexample
Increased peristalsis
- Bronchospasms Vasodilation
Large blood vessels are constricted andsmall ones are dilated
Can give a blushing effect Effects upon the patient include
Vascular endothelial cell retraction, plasmaleakage, the wheal and flare response
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Newly SynthesizedMediators
Newly synthesised from Arachdonicacid
PGE-2 : Increases the pain response PGD-2 : increases the smooth muscle
contraction Leukotrienes C4, D4 , E4 : same as
PGD2 Leukotriene B4 : chemotactic for
neutrophils
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Physical effects of mast-celldegranulation vary by tissue
Airways Decreased diameter, increased mucus secretion Expulsion of airway contents (phlegm, coughing)
Skin Edema and erythema, wheal and flare response
GI tract Increased fluid secretion, increased peristalsis Expulsion of GI contents (diarrhea, vomiting)
Blood vessels Systemic anaphylaxis Increased blood flow and permeability Edema, inflammation, increased lymph flow
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Prevention of ImmediateHypersensitivity
Treatment is by:A) blocking the events leading to the
clinical condition Anti-histamines Corticosteroids to inhibit PG and LT
B) by reversing the physical changes
that occur because of the reaction E.g., with epinephrine
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Allergen Avoidance
One needs to identify the allergen Many are common and may be
avoided somewhat
House dust mite Animal dander Many are common but are not easily
avoided
Peanuts
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Anaphylactic Shock
Pathophysiologic EffectsPathophysiologic Effects Clinical AnaphylaxisClinical Anaphylaxis
Vascular dilationVascular dilation HypotensionHypotension
Cardiac arrhythmiaCardiac arrhythmia SyncopeSyncope
BronchoconstrictionBronchoconstriction
Laryngeal edemaLaryngeal edema
Laryngeal/respiratoryLaryngeal/respiratory
obstructionobstruction Smooth muscleSmooth musclecontractioncontraction
Abdominal cramping,Abdominal cramping,vomiting diarrheavomiting diarrhea
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Type II Hypersensitivity
This is where antibody (IgG or IgM) bindsto an antigen on a cell surface
The cell is frequently part of an organ
The kidney and lung in Goodpasture's syndrome The thyroid gland
Graves or Hashimoto's diseases Or just an individual cell
Immune thrombocytopenicpurpura (ITP)
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Type II HypersensitivityMechanisms
Once bound, the antibodies can:1.Activate complement leading to cell
damage Immune thrombocytopenic purpura
(ITP) Hemolytic anemia
2.Activate ADCC for cytotoxic cellattack
Autoimmune thyroiditis
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Type II HypersensitivityMechanisms
3.Antibodies can induce phagocytosisof target cells when they act asopsonins
Extravascular autoimmune hemolyticanemia4.Bind to hormone receptors to
activate the function of a cell ororgan Hyperthyroidism
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Type II Hypersensitivity
The consequences of Type IIHypersensitivity are frequentlysevere and progressive unless
treated In some cases removal of the
antibody can be of value
Plasmapheresis for Goodpasture'ssyndrome
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Type III Hypersensitivity
This is the classic immune complex(IC) disease situation and occurswhere:
A large amount of both antigen andspecific antibody accumulate If either antibody or antigen is in
great XS large IC do not occur
As seen in serum sickness and theArthus reaction
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Type III Hypersensitivity
They also occur when theantibody/antigen complexes do notactivate the classical complement
cascade Can occur during a complement
deficiency (C1, C4, C2)
Can result in a disease similar tolupus
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Type III Hypersensitivity This situation can also occur when
immune complexes evadeactivation of the classical
Complement pathway IgA
e.g., Henoch-Schonlein purpura
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Henoch-Schonlein Purpura
IgA immunecomplexes aredeposited
Two syndromes Henoch
purpura affects
the skinand GItract
Schonlein
purpura
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Immune Complexes
The antibody forming IC is usuallyIgM, IgG or IgA
The antigen can be: a drug, from apathogen, a vaccine, host tissue, orantibody as in rheumatoid factor(Rf)
IgM antibody bound to the Fc of IgG(usually)
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Immune Complexes
Immune complexes will circulatethroughout the body and may bedeposited in various sites The kidney The joints The peripheral vasculature (skin)
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Immune Complexes
Activated C will releaseanaphylatoxins
Phagocytes will release inflammatoryand toxic molecules that will causetissue damage and plateletrecruitment
The results can be inflammation and,if appropriate, purpura
S i l h
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Systemic lupus erythematosus(SLE)
A systemic autoimmune disorder affecting The vasculature Kidneys
Skin Joints CNS
Serous tissue (serositis) Heart, spleen, lungs
S i l h
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Systemic lupus erythematosus(SLE)
Characterized by numerousautoantibodies Especially anti-nuclear antibodies
(ANA) Is often described as the typical Type
III Hypersensitivity disease
But also has elements of Type IIHypersensitivity May have positive Coombs test
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Lupus
S t i l th t
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Systemic lupus erythematosus(SLE)
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Arthus reaction
This is a local tissue bound Type IIIHypersensitivity reaction
It usually occurs after repeatedintramuscular (IM) injections of antigens
It can induce pain and even necrosis
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Type III Hypersensitivity
Arthus reaction Local
immunecomplexdepositiondue to
immunization
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Arthus Reaction
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Immune Complex Mediated
Disease Serum sickness This is due to the development of
Type III Hypersensitivity
It is a problem when administeringequine antiserum for bacterialtoxins such as:
Diphtheria Tetanus
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Serum sickness After repeated administration of horse
antiserum individuals developed Arthritis
Myalgia Vomiting Malaise
Rashes Fever
Contrasts Between
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Contrasts BetweenHypersensitivity Types II and III
Although both can affect the
kidneys the mechanism aredifferent For example, both immune
complexes and anti-GBMantibodies can accumulate in thekidneys but the effects aredissimilar
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Goodpastures Syndrome
Rapid progressive glomerulonephritisdue to anti-glomerular basementmembrane antibody, plus
pulmonary hemorrhage Antibody cross reacts with the GBM
and alveolar basement membrane
(Type II Hypersensitivity)
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Goodpastures Syndrome
Both lupus and Goodpastures willactivate complement by theclassical pathways (C1, C2 and C4
levels my be lower than NR) Both diseases will cause renal
disease
The actual effects caused byantibodies are different
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Goodpastures Syndrome
Goodpastures syndrome IFmicroscopy will reveal lineardeposition of IgG along the GBM
Lupus however shows clumps of immune complexes deposited onthe GBM that have a lumpy-
bumpy appearance
Type IV (Delayed Type)
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Type IV (Delayed Type)Hypersensitivity (DTH)
This was originally defined as A hypersensitivity reaction that took
more than 12 hours to develop
This is typified by the classical skinreaction which occurs in responseto
Nickel, poison ivy, latex, for example
Type IV (Delayed Type)
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Type IV (Delayed Type)Hypersensitivity (DTH)
It can also take place in internalorgans The liver, gut
The reaction is often chronic if internal and can last for years
It occurs in conditions where the
antigen is unknown or disputed, forexample sarcoidosis and perhapsCrohn's disease
Type IV (Delayed Type)
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Type IV (Delayed Type)Hypersensitivity (DTH)
It occurs in response to somechronic infections, particularlyintracellular ones, e.g.,Mycobacterium tuberculosis (TB)
It can also occur during graft
rejection against solid organtransplants Liver, kidneys, heart
It is a major mechanism forattacking solid tumors
Delayed Type
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Delayed TypeHypersensitivity
It is an immune response mediatedmostly by CD4+ T cells
t Th1 Also CD8+ T cells can contribute
The effector cells are largely M
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DTH
Many of the substances inducingcontact hypersensitivity arehaptens
Small molecules which are notantigenic until bound to a largerprotein, e.g., nickel
They can complex with skin
molecules Internalized by Langerhan's cells in
the epidermis
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DTH
This complex is then presented with MHCClass II To CD4+ T cells
Release cytokines ( TNF- , IL-2,IFN- )
Approximately 24-48 hours after exposure,M accumulate
The M release lysozomal enzymes Redness and pustules result
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DTH
The M can also release TNF- Active oxygen species
The cytokines released from the Tcells will also have severe effectsupon the skin
TNF-
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Chronic DTH
The M change morphology They fuse to form giant cells
These become focused around sites
of stimulation To form granulomas
The tissue at the site of chronic DTHis eventually replaced by fibroustissue Fibrosis
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Hypersensitivity and Drugs
Type IV responses are frequently dueto topical medications
A suspected sensitivity can beconfirmed by applying a weaksolution to the skin in a patch test.
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Contact Hypersensitivity